Overall IRPG objective is to timely verify potentially breakthrough emerging strategies based on the use of novel immunomodulatory interventions, by multidisciplinary translational research (pre- clinical) and pilot clinical trials to achieve our final goal of successful islet replacement and preservation of beta cell mass in patients with Type 1 diabetes. Current protocols of immunosuppression impose increased metabolic demand (insulin secretion) to maintain normoglycemia that are deleterious in a situation of reduced beta cell mass, such as an islet cell transplant. In addition non-specific inflammatory events and ischemia/reperfusion-like phenomena can contribute to a significant early loss of implanted islets. Our CENTRAL HYPOTHESIS is that islet transplants will be consistently successful in patients receiving immunomodulatory treatments aimed at preventing early inflammatory events while avoiding beta cell toxicity and the increased metabolic demand imposed by conventional immunosuppression. Our pre- clinical preliminary results indicate that recently developed non- diabetogenic immunomodulatory strategies, based on blockade of the CD40- CD154 T lymphocyte costimulatory pathway, promote islet engraftment and long term function. Blockade of this early costimulatory pathway represents a powerful treatment option for prevention of islet allograft failures in patients with Type I diabetes, since it might allow for prevention of rejection, autoimmunity and inflammation at the site of islet implantation, all of which are thought to contribute to the poor outcome of clinical islet cell transplants. Encouraging results also suggested that donor-specific bone marrow infusion significantly improve the outcome of solid organ grafts. Additional evidence indicates that bone marrow transplantation might prevent onset/recurrence of autoimmunity. It is now critical to test, in pilot clinical trials, immunomodulatory protocols designed to maximize engraftment and survival of islet transplants. We propose: Specific Aim number 1: To determine whether anti-CD154 antibody (5c8) will allow islet allograft survival in patients with Type 1 diabetes. Specific Aim number 2: To determine whether co-transplantation of donor bone marrow cells will further improve islet allograft survival and allow discontinuation of anti-CD154 antibody at 1 year. Specific Aim number 3: To assess the functional and metabolic capacity of successful intrahepatic islet allografts. Specific Aim number 4: To study the immune profile/function of patients receiving anti-CD154 therapy and/or donor bone marrow infusion.